US006046183A United States Patent (19) 11 Patent Number: 6,046, 183 Gormley et al. (45) Date of Patent: Apr. 4, 2000 54 METHOD OF SYNERGISTIC TREATMENT WO 91/OO732 1/1991 WIPO. FOR BENIGN PROSTATIC HYPERPLASA WO 91/OO733 1/1991 WIPO. WO 93/19758 10/1993 WIPO. (75) Inventors: Glenn J. Gormley; Elizabeth Stoner, OTHER PUBLICATIONS both of Westfield, N.J. Nieschlag et al., Z. Klin. Chem. u. klin. Biochem. (1972), Assignee: Merck & Co., Inc., Rahway, N.J. pp. 164-168, "Radioimmunoassay for plasma testosterone'. Kumamoto et al., Hinyokika Kiyo, vol. 33 (1987), pp. Appl. No.: 09/027,105 1921-1922, “Clinical efficacy of oxendolene (antiandrogen) and bunaZosin hydrochloride (alpha-adrenergic blocker) . Filed: Feb. 20, 1998 Kumamoto et al., Hinyokika Kiyo, vol. 33 (1987), pp. Related U.S. Application Data 1921-1922, “Clinical efficacy of oxendolene (antiandrogen) Continuation of application No. 08/428,595, Apr. 25, 1995, and bunaZosin hydrochloride (alpha-adrenergic blocker) . Pat. No. 5,753,641, which is a continuation of application No. 08/201,063, Feb. 24, 1994, abandoned, which is a Caine et al., Chem. Abstracts, vol. 102(11):90035s, “The continuation of application No. 08/022,805, Feb. 22, 1993, effect of nicergoline on the lower urinary tract muscle' Date abandoned, which is a continuation of application No. needed. 07/846,153, Mar. 11, 1992, abandoned, which is a continu ation-in-part of application No. 07/672,511, Mar. 20, 1991, Caine et al., British J. of Urology, vol. 48 (1976), pp. abandoned. 255-263, “The use of alpha-adrenergic blockers in benign prostatic obstruction'. 51 Int. Cl." .......................... A61K 31156; A61K 31/58; Neri et al., Investigative Urology, vol. 10 (1972), pp. A61K 31/505 123-130, “Effects of novel nonesteroidal antiandrogen on 52) U.S. Cl. .......................... 514/170; 514/176; 514/260; canine prostatic hyperplasia”. 514/257 The Daily, May 7, 1996, “New data on Proscar, Abbott's 58 Field of Search ..................................... 514/176, 260, Hytrin show conflicting results’. 514/257, 170 Wall Street Journal, May 7, 1996, p. B4, “Study finds References Cited Abbott’s prostate drug is much more effective than Mer 56) cks'. U.S. PATENT DOCUMENTS US News & World Report, May 20, 1996, “Zapping a problem prostate'. 3,511,836 5/1970 Hess ..................................... 260/256.4 3,527,761 9/1970 Archibald et al. ... 260/293 Lepor, N. Engl. 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J. of Med., vol. 335 (1996), pp. 585–588, 4,732,897 3/1988 Cainelli et al. ....... ... 514/222 “Treatment of benign prostatic hyperplasia”. 4,760,071 7/1988 Rasmusson et al. ... 514/284 CA:109:163450 (Iepor et al.), 1988. 4,845,104 7/1989 Carlin et al. ............................ 514/284 4,859,681 8/1989 Rasmusson et al. .................... 514/284 Primary Examiner. Theodore J. Criares 4,882,319 11/1989 Holt et al.......... ... 514/119 Attorney, Agent, or Firm-Catherine D. Fitch 4,888,336 12/1989 Holt et al... ... 514/278 57 ABSTRACT 4,910,226 3/1990 Holt et al...... ... 514/573 5,212,176 5/1993 Kynclet al. .. ... 514/254 Disclosed is an improved treatment for men with benign FOREIGN PATENT DOCUMENTS prostatic hyperplasia (BPH), involving combination therapy of a 5C.-reductase inhibitor, e.g. a 17 B-Substituted 0 004 949 10/1979 European Pat. Off.. 4-azasteroid, a 17B-Substituted non-azasteroid, 173-acyl-3- 0 155 096 9/1985 European Pat. Off.. carboxy-androst-3,5-diene, benzoylaminophenoxybutanoic O 173 516 3/1986 European Pat. Off.. 0 277 002 8/1988 European Pat. Off.. acid derivative, fused benz(thio)amide or cinnamoylamide 0 289 327 11/1988 European Pat. Off.. derivative, aromatic 1,2-diethers or thioethers, aromatic 0 291 245 11/1988 European Pat. Off.. ortho acylaminophenoxy alkanoic acids, ortho thioalkyla O 314199 5/1989 European Pat. Off.. cylaminophenoxy alkanoic acids, pharmaceutically accept O 343 954 5/1989 European Pat. Off.. able Salts and esters thereof, and particularly finasteride, in 0.375 344 11/1989 European Pat. Off.. combination with an O-adrenergic receptor blocker, i.e., 0.375 345 6/1990 European Pat. Off.. teraZosin. The combination provides therapy at the molecu 0.375 347 6/1990 European Pat. Off.. lar level for the underlying cause of the disease as well as 0.375 349 6/1990 European Pat. Off.. providing Symptomatic relief. Pharmaceutical compositions 68/3204 1/1969 South Africa. 1156973 7/1969 United Kingdom. useful for treatment are also disclosed. 2007656 5/1979 United Kingdom. WO 90/10462 9/1990 WIPO. 2 Claims, No Drawings 6,046, 183 1 2 METHOD OF SYNERGISTIC TREATMENT SUMMARY OF THE INVENTION FOR BENIGN PROSTATIC HYPERPLASA By this invention there is provided a method of treating CROSS REFERENCE TO RELATED benign prostatic hypertrophy patients being treated with a APPLICATIONS 4-aza Steroid 5C.-reductase inhibitor and are experiencing inadequate Symptomatic relief who are in need of Such This application is a continuation of U.S. Ser. No. 08/428, treatment comprising the Step of administering in combina 595, filed Apr. 25, 1995, now U.S. Pat. No. 5,753,641, which tion to Such patients therapeutically effective amounts of a in turn was a continuation of U.S. Ser. No. 08/201,063, filed 5C-reductase inhibitor, a 17B-Substituted 4-azasteroid, a Feb. 24, 1994, now abandoned; which in turn was a file 17 B-substituted non-azasteroid, 173-acyl-3-carboxyandrost wrapper continuation under 37 CFR 1.62 of U.S. Ser. No. 3,5-diene, benzoylaminophenoxybutanoic acid derivative, 08/022,805, filed Feb. 22, 1993, now abandoned; which in fused benz(thio)amide or cinnamoylamide derivative, aro turn was a file wrapper continuation under 37 CFR 1.62 of matic 1,2-diethers or thioethers, aromatic ortho acylami U.S. Ser. No. 07/846,153, filed Mar. 11, 1992, now aban nophenoxy alkanoic acids, ortho thioalkylacylaminophe doned; which in turn was a continuation-in-part of U.S. Ser. noxy alkanoic acids, pharmaceutically acceptable Salts and No. 07/672,511, filed Mar. 20, 1991, now abandoned. 15 esters thereof, and particularly an O-adrenergic receptor BACKGROUND OF THE INVENTION blocking agent, also termed herein “C.-blocker'. 1. Field of the Invention Thus, the combined effect of a 5C.-reductase inhibitor in This invention relates to a new method of treatment for inhibiting DHT production in the prostate and the patients, i.e. men having benign prostatic hyperplasia C.-adrenergic receptor blocker, i.e. terazosin, will result in a (BPH), involving combination therapy of administering greater effect on Suppressing the growth and Symptomatic therapeutically effective amounts of a 5C.-reductase inhibitor relief of enlarged prostate than either agent by itself. in combination with an O-adrenergic receptor blocker. BRIEF DESCRIPTION OF THE INVENTION 2. Background of the Invention AND PREFERRED EMBODIMENTS 25 Benign prostatic hyperplasia (BPH) affects a substantial In one preferred aspect, the present invention provides an number of males over the age of 50 and usually requires effective method of treating BPH in patients in need of Surgery in advanced Stages for relief. Symptomatic relief by administerstering therapeutically It is known that testosterone (T) is secreted by the testes and adrenal glands but can undergo a 5C-reductase mediated effective amounts of the C-blocker in association with a conversion to dihydrotestosterone (DHT) in peripheral sites 5C.-reductase inhibitor or pharmaceutical composition including the liver, Skin, and prostate. DHT is preferentially thereof. The active compounds may be administered bound by the nucleus of prostatic cells thus indicating that together or in any order, as discussed hereinafter. DHT, rather than T, is the primary androgen required by the By the term “patients in need of Such treating” is meant prostate for its growth and function. This led to the hypoth male patients with functioning gonads who are being treated esis that, by inhibiting 5C.-reductase, the formation of DHT 35 with a 5C.-reductase inhibitor in a therapeutic program could be curtailed and hopefully prostate regression designed to combat benign prostatic hyperplasia (BPH) and obtained. are discovered to be in need of Symptomatic relief. Finasteride, 17B(N-t-butyl)carbamoyl-4-aza-5C.-androst The use of therapeutically effective amounts of the 1-en-3-one, was developed as a compound which was found 40 5C-reductase inhibitor and the C-blocker in accordance to inhibit 5C.-reductase and exhibit positive effects against with this invention effectively treats the adverse symptoms benign prostatic hyperplasia. Finasteride is a 4-azasteroid of BPH including nocturia, hesitancy, decreased urinary and a competitive, inhibitor of the enzyme. It shows no flow, and the like. affinity for the androgen receptor and So would not be It has been shown that Stimulation of C.-adrenoreceptors expected to interfere with the binding and action of T in 45 contributes to the obstruction of benign prostatic hyperplasia those tissues, Such as muscle, which respond to T, and thus (See M. Caine, et al., Br. J. Urol, Vol. 48, pp. 255–263 should not result in feminizing characteristics.